Process for the preparation of 2-acylhy-drazino-5-nitrosotropone derivatives



ing potent antimicrobial activities.

United States Patent 3,121,726 PROCESS FOR THE i REFARA'HQN 0F 2 ACYLHY- DRAZiNtB-NHTRKEGTRQEU DEREVATIVES Genshnn Sunagawa, h/iasao Arahawa, Yasunobu Sato, and Haruhiko Minaliami, ail of ShinagaWa-ku, Tokyo, Japan, assignors to danityo Company, Limited, Tokyo, Ia an Ni? Drawing. Filed Bee. 11, 1961, her. No. 15%,558 Claims priority, appiication Japan Dec. 17, 1960 6 Ciairns. (G. 259-295) This invention relates to Z-acy-lhydrazino-S-nitrosotropone derivatives and process for preparing thereof. More particularly, it relates to new 2-acylhydrazino-S- nitrosotropone derivatives having the formula:

-NHNH on C p-chlorophenyl, tolyl, anisyl or p-dirnethylaminophenyl and unsubstituted or substituted heterocyclic group such as 2-pyridyl, 3-pyridy1, 4-pyridyl, pyrazinyl, 5-nitro-2- furyl, 2-indolyl, 4-pyridyl N-oxide or 4-pyridyl l-rnethyl nitrate out The 2-acylhydrazino-5'-nitrosotropone derivatives of this invention exist in tautomerisrn between forms The above-mentioned Z-acylhydrazino-S-nitrosotropone derivatives of this invention are new compounds possess- For example, 2-isonicotinoylhydrazino-S-nitrosotropone of this invention completely inhibits growth of Micrococcus tuberculosis cultivated on Kirchner medium at a concentration of 0.78 meg/ml. They are therapeutically useful in view of their low toxicities.

It is an object of this invention to provide novel group of compounds of therapeutic use as described above. It is another object of this invention to provide process for preparing such compounds. Other objects of this invention will be apparent hereinafter.

According to the present invention, 2-acylhydrazino-5- wherein X has the meanings given above with canboxylic.

acid hydrazides having the formula:

NH NH-COR wherein R has the meanings given above.

In carrying out the process according to the present invention, the reaction is preferably effected by heating the reactants in an inert aqueous or non-aqueous organic solvent such as methanol, aqueous methanol, ethanol or aqueous ethanol for about 5 to 15 minutes. After completion of the reaction, the reactionproduct is isolated from the reaction mixture by one of the conventional procedures. For example, after completion of the reaction, the reaction mixture is cooled and the precipitated product is recovered by filtration. Alternatively, after completion of the reaction, the reaction mixture is concentrated under reduced pressure, the concentrated mixture is cooled and then the precipitated product is recovered by filtration.

As compounds used as canboxylie acid hydrazide in the process according to the present invention, there may be mentioned formic acid hydrazide, acetic acid hydrazide, u-butyric acid hydrazide, iso-valeric acid hydrazide, n-octanoic acid hydrazide, u-nonanoic acid hydrazide, pnitrophenylacctie acid hydrazide, lactic acid hydrazide, phenoxyacetic acid hydrazide, benzoic acid hydrazide, p-nitrobenzoic acid hydrazide, p-toluic acid hydrazide, p-anisic acid hydrazide, p-dimethyl aminobenzoic acid hydrazide, isonicotinic acid hydrazide, nicotinic acid hydrazide, picolinie acid hydrazide, pyrazinoic acid hydrazide, 5'-nitro-2-furoic acid hydrazide, indole-Z-carboxylic acid hydrazide, isonicotinic acid hydrazide N- oxide audisonicotinic acid hydrazide l-methyl nitrate.

As compounds used as S-nitrosotropolone derivatives mentioned above there may be mentioned S-nitrosotropolone, S-bromo-5-nitrosotropolone, 3-phenyl-5-nitrosotropolonc and 3-rnethyl-S-nitrosotropolone.

Representative of the 2-acylhydrazino-S-nitrosotropone derivatives obtained by the process according to the present invention are 2-forrnyl hydraZino-5-.nitrosotro pone, 2-acety1 hydrazino-S-nitrosotropone, Z-butyroyl hydrazine-5-nitrosotropone, 2-iso-valeroyl hydrazine-5- nitrosotropone, 2-n-octanoyl hydrazino-S-nitrosotropone, Z-n-nonanoyl hydrazine 5' nitrosotropone, 2-p-nitrophenylacetyl' hydrazino-S-nitrosotropone, Z-lactoyl hydrazino-S-nitrosotropone, Z-p-dirnethyl aminobenzoylhydrazine-5-nitrosotropone, Z-phenoxy acetylhydrazino- S-nitrosotropone, Z-benzoylhydrazino 5 nitrosot-ropone, 2-p-nitrobenzoylhydrazino-S nitrosotropone, 2-p-toluoylhydrazino 5 nitrosotropone, 2 p anisoy-lhyd-razino-S nitrosotropone, 2 p dimethylaminobenzoylhydrazino-5- nitrosotropone, Z-isoriicotinoylhydrazino 5 nritrosotropone, Z-nicotinoylhydrazino 5 -nitrosotropone, 2-picolinoyl hydrazine-5-nitrosotropone, Z-pyrazinoylhydrazino- S-nitrosotropone, 2-(5-nitro2-furoy1) hydrazino-5-nitrosotropone, 2-indolylcarbonyihydrazino-S-nitrosotropone, 2 isonicotinoylhydrazino 5 nitrosotropone N-oxide, 2-isonicotinoylhydrazino-S-nitrosotropone l-rnethyl nitrate, Z-benzoylhydrazino 5 nitroso 7 bromotropoue,

. 6 The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given by Way of illustration and not of limitation.

' EXAMPLE 1 Preparation of Z-Benzoylhydrazin-5-Nilr0s0tr0p0ne To a hot solution of 300 mg. of S-nitrosotropolone in 30 ml. of ethanol is added a solution of 280 mg. of benzoic acid hydrazide dissolved in 20 ml. of 60% aqueous ethanol. The resulting mixture is boiled for about minutes. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to crystallize orange yellow crystals. The product is recrystallized from 85% aqueous ethanol to give orange yellow needles, MP. 192- 193 C. (with decomposition).

Analysis.Calcd for C I-1 N 0 C, 62.45; H, 4.12; N. 15.61. Found: C, 62.04; H, 4.25; N, 15.66.

It is easily soluble in alkaline aqueous solution and sparingly soluble in water.

U.V. spectrum: A223, 226.5 m (log 6 4.26); 280 m (log e 4.16); 396 111;; (log 6 4.27)

EXAMPLE 2 Z-p-N itrobenzoy lhydrazin0-5 -N i trosotropone The procedure of Example 1 is repeated except that 405 mg. of p-nitrobenzoic acid hydrazide is used instead of benzoic acid hydrazide. The resulting product is dis solved in hot pyridine, water is added to the solution and the precipitate thus formed is filtered to obtain 300 mg. of orange yellow microcrystals decomposing at 199200 C.

Analysis-Calcd for C H O N C, 58.01; H, 3.84; N, 17.87. Found: C, 58.10; H, 3.87; N, 17.63.

U.V. spectrum: A539? 246 m (log e 4.44); 396 m (log 6 4.34); 535 m (log 6 4.07); 565 m (log 6 4.04) shoulder EXAMPLE 3 2-p-Toluoylhydrazin0-5-Nitr0s0tr0p0ne The procedure of Example 1 is repeated except that 330 mg. of p-rnethylbenzoic acid hydrazide is used instead of benzoic acid hydrazide. The product thus obtained is recrystallized from aqueous dioxane to obtain 172 mg. of orange needles decomposing at 219-220 C.

Analysis.-Calcd for C H O N C, 63.59; H, 4.63; N, 14.83. Found: C, 63.69; H, 4.64; N, 14.97.

U.V. spe)ctrum: X212? 232 m (10g 6 4.37); 396 m (log V EXAMPLE 4 Z-p-Anisoylhydrazino-S-Nitrosotropone To a hot solution of 300 mg. of S-nitrosotropoloue in 30 m1. of ethanol is added a solution of 370 mg. of p-anisic acid hydrazide dissolved in ml. of ethanol. The resulting mixture is boiled for 15 minutes. After completion of the reaction, the reaction mixture is cooled to room temperature and the crystals thus separated are recrystallized from dioxane to obtain orange yellow microcrystals decomposing at 230231 C.

Analysis.-Calcd for C H O N C, 60.19; H, 4.38; N, 14.04. Found: C, 60.54; H, 4.24; N, 13.91.

U.V. spsetrumz A232? 25.35 m (log e 4.34); 400 m (log EXAMPLE 5 Z-p-Nitrophenylacetylhydrazirto-S-Nitrosotropone The procedure of Example 4 is repeated except that 500 V mg. of p-nitrophenylacetic acid hydrazide is used instead of p-anisic acid hydrazide. The product thus obtained is recrystallized from aqueous dioxane to obtain 250 mg. of yellow scaly crystals decomposing at 212 C.

d. Analysis.-Calcd for C H O N C, 54.88; H, 3.68; N, 17.07. Found: C, 54.81; H, 3.74; N, 16.81.

U.v.4spe etrum: x532? 271 m (log 6 4.45); 382 m (log EXAMPLE 6 2 -p-Dimethy lam inobenzoy lhy drazino-S -N i trosotropone The procedure of Example 4 is repeated except that 350 mg. of p-dimethylaminobenzoic acid hydrazide is used instead of p-anisic acid hydrazide. The resulting product is recrystallized from dioxane to obtain 500 mg. of reddish violet needles decomposing at 212222 C.

Analysis.Calcd for C H O N C, 60.63; H, 5.16; 'N, 17.94. Found: C, 60.24; H, 5.47; N, 17.27.

EXAMPLE 7 Z-Isonicotinoylhydrazino-S-Nitros0tr0p0ne U.V. spectrum: A532? 266 m (log 6 4.20); 425 m (log 6 3.95) The product is sparingly soluble in water and ethanol and is easily soluble in alkaline aqueous solution.

EXAMPLE 8 Z-Nz'cotinoylhydrazino-5-Nitr0s0trop0ne The procedure of Example 7 is repeated except that the same amount of nicotinic acid hydrazide is used instead of isonicotinic acid hydrazide to obtain 250 mg. of orange microcrystals decomposing at 23023l C.

Analysis.-Calcd for C H O N C, 57.77; H, 3.73; N, 20.73. Found: C, 57.78; H, 3.95; N, 20.60.

U.V. spectrum: k3,? 269 m (log 6 4.14); 394 m (log 6 4.19); 54.5 In (log 6 4.98)

EXAMPLE 9 2-Picolin0ylhya'razin0-5-Nitr0s0trop0ne The procedure of Example 7 is repeated except that the same amount of picolinic acid hydrazide is used instead of isonicotinic acid hydrazide. The product thus formed is recrystallized from dioxane to obtain 250 mg. of yellow crystals decomposing at 225 C.

Analysis.-Calcd for C H O N C, 57.77; H, 3.73; N, 20.73. Found: C, 57.77; H, 3.53; N, 20.81.

U.V. spectrum: A532? 270 m (log e 4.18); 392 m (log EXAMPLE 10 Z-Pyrazinoylhydrazino-S-Nitrosotropone The procedure of Example 7 is repeated except that 310 mg. of pyrazinoic acid hydrazide is used instead of isonicotinic acid hydrazide to obtain 240 mg. of yellow microcrystals decomposing at 255 C.

Analysis.Calcd for C H O N C, 53.14; H, 3.34; N, 25.82. Found: C, 53.42; H, 3.50; N, 25.94.

U.V. spectrum: A513, 268 m (log 6 4.30); 392 m (log EXAMPLE 11 Z-Isonicotinoylhydrazino-5-Nitros0tr0pone N-oxide To a hot solution of 600 mg. of S-nitrosotropolone in 60 m1. of ethanol is added a solution of 600 mg. of isonicotinic acid hydrazide N-oxide dissolved in'20 ml. of water and the mixture is boiled on Water bath for 10 minutes. After completion of the reaction, the reaction mixture is cooled to room temperature to crystallize orange crystals decomposing at 220 C.

Analysis.-Calcd for C I- 04M C, 54.55; H, 3.52; N, 19.58. Found: C, 54.91; H, 3.73; N, 19.60.

U.V. spectrum: x552? 277 m (log 6 4.34); 405 my (log e 4.18); 530 m (log 6 4.30); 5621n (log 6 4.28)

EXAMPLE 12 2 -lsnic0!in0yi hydrazin 0-5 -N i trosotropone 1 -M ethyl Nitrate The procedure of Example 11 is repeated except that 900 mg. of isonicotinic acid hydride 1-methyl nitrate is used instead of isonicotinic acid hydrazide N-oxide to obtain 400 mg. of yellow microcrystals decomposing at 189-190" C.

Analysis.-Ca1cd for C H O N C, 48.42; H, 3.77; N, 20.17. Found: C, 48.13; H, 3.87; N, 19.86.

U.V. spectrum: A512 269 mu (log 6 4.33); 412 111p (log 6 3.95); 550 m (log 5 4.25); 583 m (log 6 4.16) shoulder EXAMPLE 13 2 (5 -N i tro-Z-F uroyl H ydrazino-S -N itrosotropoize To a hot solution of 300 mg. of S-nitrosotropolone in 40 ml. of methanol is added a solution of350 mg. of 5- nitro-S-furancarboxylic acid hydrazide dissolved in 13 ml. of 75% aqueous methanol and the mixture is boiled on water bath for minutes. After completion of the reaction, the reaction mixture is cooled to room temperature and the crystals thus obtained are recrystallized from 73% aqueous solution to obtain orange needles melting at 243244 C. (with decomposition).

Analysis.Calccl for C H O N C, 47.37; H, 2.65; N, 18.42. Found: C, 47.36; H, 2.67; N, 18.26.

U.V. spectrum: 1223. 291 (log 6 4.25); 400 m (log e 4.23); 540 III/.4 (log 6 3.86); 570 m (log 6 3.81) shoulder EXAMPLE l4 2- 2 -1 nd olyl carbonyl H ydrazz'no-S -N irrosotropone To a hot solution of 600 mg. of S-nitrosotropolone in 60 ml. of methanol is added a solution of 790 mg. of indole-Z-carboxylic acid hydrazide dissolved in 80 ml. of methanol and the mixture is boiled on a water bath for 10 minutes. After completion of the reaction, the reaction mixture is concentrated under reduced pressure to a volume of 50 ml., and then the separated crystals are recrystallized from aqueous pyridine to obtain 610 mg. of reddish orange microcrystals decomposing at 234 235 C.

Analysis.-Calcd for C H O N C, 62.33; H, 3.92; N, 18.18. Found: C, 62.67; H, 4.06; N, 17.89.

U.V. spectrum: A522? 234 m (log 6 4.34) shoulder; 285

my (log e 4.30); 430 m (log 6 4.36)

To a hot solution of 300 mg. of S-nitrosotropolone in 30 ml. of ethanol is added a solution of 234 mg. of formic acid hydrazide dissolved in 10 ml. of water and the mixture is boiled on a Water bath for 15 minutes. After completion of the reaction, the reaction mixture is concentrated under reduced pressure and the crystals thus obtained are recrystallized from 40% aqueous ethanol to produce 200 mg. of yellowish brown needles decomposing at 210 C.

Analysis.-Calcd for C l-1 0 14 C, 49.74; H, 3.65; N, 21.76. Found: C, 49.87; H, 3.71; N, 21.70.

U.V. spe)ctrum: A523? 270 m (log 6 4.16); 378 m (log 5 EXAMPLE 16 2-A cety1hydrazino-S-Nitrosotrop on e The procedure of Example 15 is repeated except that 170 mg. of acetic acid hydrazide is used instead of formic acid hydrazide. The resulting product is recrystallized from 50% aqueous ethanol to obtain 160 mg. of yellow needles decomposing at 185 C.

Analysis.Calcd for C l-1 0 14 C, 52.17; H, 4.38; N, 20.28. Found: C, 51.93; H, 4.45; N, 20.72.

EXAMPLE 17 2-n-B utyroylhydmzino-S -N itrosotro pone EXAMPLE 18 2-is0-Valeroylhydrazin0-5-Nitr0sotrop one The procedure of Example 15 is repeated except that 250 mg. of iso-valeric acid hydrazide'is used instead of formic acid hydrazide. The product thus produced is recrystallized from 40% aqueous ethanol to obtain 200 mg. of yellow needles melting at 167-168 C. (with decomposition) Analysis.Calcd for C I-1 0 14 C, 57.82; H, 6.07; N, 16.86. Found: C, 57.77; H, 6.01; N, 16.99.

EXAMPLE 19 Z-n-Oclanoylhydrazin0-5-Nitr0sotr0p0ne The procedure of Example 15 is repeated except that 350 mg. of n-octanoic acid hydrazide is used instead of formic acid hydrazide. The product thus produced is recrystallized from 50% aqueous ethanol to obtain 270 mg. of yellow scaly crystals melting at 143144 C. (with decomposition).

Analysis.-Calcd for C H O N C, 61.84; H, 7.27; N, 14.42. Found: C, 62.10; H, 7.59; N, 14.95.

EXAMPLE 20 2-n-N0ncmoylhydmzin0-5-Nitr0sotrop0ne The procedure of Example 15 is repeated except that 380 mg. or" n-nonanoic acid hydrazide is used instead of formic acid hydrazide. The product thus produced is recrystallized from 70% aqueous ethanol to obtain 400 mg. of yellow microcrystals decomposing at C.

Analysis.-Calcd for C H O N C, 62.93; H, 7.59; N, 13.76. Found: C, 62.85; H, 7.56; N, 13.70.

A53 266 my. (log 6 4.15); 384 my (log U.V. spectrum:

EXAMPLE 21 Z-Phenoxyacelylhydmziizo-5-Nitr0s0tr0pone To a hot solution or 300 mg. of 5-nitrosotropolone in 30 ml. of ethanol is added a solution of 345 mg. of phenoxyacetic acid hydrazide dissolved in 10 ml. of ethanol and the mixture is boiled on a water bath for 10 minutes. After completion of the reaction, the reaction mixture is concentrated under reduced pressure and the crystals separated are recrystallized from aqueous dioxane to obtain mg. of yellow needles melting at 205-206" C. (with decomposition).

7 Analysis.Calcd for C H O N C, 60.19; H, 4.38; N, 14.04. Found: C, 60.05; H, 4.45; N, 14.11.

U.V. spectrum: R223? 268 m (log e 4.15); 274 m (log EXAMPLE 22 2-Lact0ylhydrazin0-5-Nitr0s0tr0p0ne wherein X is a member selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy and phenyl and R is a member selected from the group consisting of 2-, 3- and 4-pyridyl, 4-pyridyl l-oxide, 4-pyridyl l-methyl nitrate and pyrazinyl.

2. 12-isonicotinoylhydrazino-5-nitrosotropone.

3. 2-isonicotinoylhydrazino-5-nitrosotropone N-oxide.

4. A process for preparing a compound having the formula ON/| o k NHNHC o R wherein X is a member selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy and phenyl and R is a member selected from the group consisting of 2-, 3- and 4-pyridy1, 4-pyridyl l-oxide, 4-pyridyl l-methyl nitrate and pyrazinyl, comprises reacting a compound having the formula wherein X has the same meanings as described above with a compound having the formula wherein R has the same meanings as described above.

5. Process for preparing 2-isonicotinoylhydrazino-S- nitrosotropone. which comprises reacting 5-nitrosotropolone with isonicotinic acid hydrazide.

6. Process for preparing 2-isonicotinoylhydrazino-S- nitrosotropone N-oxide which comprises reacting 5-nitrosotropolone with isonicotinic acid hydrazide N-oxide.

No references cited. 

1. A COMPOUND HAVING THE FORMULA 